-
Medicina (Kaunas, Lithuania) Sep 2023Colorectal cancer is the second leading cause of cancer-related mortality worldwide. Numerous pathophysiological mechanisms, such as abnormal cell proliferation, cell... (Review)
Review
Colorectal cancer is the second leading cause of cancer-related mortality worldwide. Numerous pathophysiological mechanisms, such as abnormal cell proliferation, cell differentiation, resistance to apoptosis, invasion of structures adjacent to colorectal tumor cells, and distant metastasis, are involved in colorectal carcinogenesis. These processes are initiated by the complex interaction of a number of genetic and environmental factors, including sedentary lifestyle, obesity, alcohol consumption, smoking, or gut microbiota. Despite the significant progress achieved in the diagnostic and therapeutic management of patients with colorectal cancer, there has been recently a noteworthy increase in the incidence of colorectal cancer in individuals below the age of 50 years. Early-onset colorectal cancer has a different frequency of oncogenic mutations, a higher prevalence of mucinous histology, a distinct deoxyribonucleic acid (DNA) methylation profile, a more distal location, and lower survival rates. A significant improvement in the prognosis of these patients can be achieved through the detection and removal of modifiable risk factors, along with the implementation of personalized screening strategies for individuals at high risk for this malignancy. Furthermore, gaining comprehension of the pathophysiological mechanisms by which these risk factors contribute to the process of oncogenesis may facilitate the discovery of novel therapeutic targets.
Topics: Humans; Middle Aged; Carcinogenesis; Cell Transformation, Neoplastic; Risk Factors; Alcohol Drinking; Colorectal Neoplasms
PubMed: 37763765
DOI: 10.3390/medicina59091646 -
Role of the Gut Microbiota and Its Metabolites in Tumorigenesis or Development of Colorectal Cancer.Advanced Science (Weinheim,... Aug 2023Colorectal cancer (CRC) is the most common cancer of the digestive system with high mortality and morbidity rates. Gut microbiota is found in the intestines, especially... (Review)
Review
Colorectal cancer (CRC) is the most common cancer of the digestive system with high mortality and morbidity rates. Gut microbiota is found in the intestines, especially the colorectum, and has structured crosstalk interactions with the host that affect several physiological processes. The gut microbiota include CRC-promoting bacterial species, such as Fusobacterium nucleatum, Escherichia coli, and Bacteroides fragilis, and CRC-protecting bacterial species, such as Clostridium butyricum, Streptococcus thermophilus, and Lacticaseibacillus paracasei, which along with other microorganisms, such as viruses and fungi, play critical roles in the development of CRC. Different bacterial features are identified in patients with early-onset CRC, combined with different patterns between fecal and intratumoral microbiota. The gut microbiota may be beneficial in the diagnosis and treatment of CRC; some bacteria may serve as biomarkers while others as regulators of chemotherapy and immunotherapy. Furthermore, metabolites produced by the gut microbiota play essential roles in the crosstalk with CRC cells. Harmful metabolites include some primary bile acids and short-chain fatty acids, whereas others, including ursodeoxycholic acid and butyrate, are beneficial and impede tumor development and progression. This review focuses on the gut microbiota and its metabolites, and their potential roles in the development, diagnosis, and treatment of CRC.
Topics: Humans; Gastrointestinal Microbiome; Colorectal Neoplasms; Carcinogenesis; Cell Transformation, Neoplastic; Bacteria; Escherichia coli
PubMed: 37263983
DOI: 10.1002/advs.202205563 -
Cell Aug 2023Cancer driver events refer to key genetic aberrations that drive oncogenesis; however, their exact molecular mechanisms remain insufficiently understood. Here, our...
Cancer driver events refer to key genetic aberrations that drive oncogenesis; however, their exact molecular mechanisms remain insufficiently understood. Here, our multi-omics pan-cancer analysis uncovers insights into the impacts of cancer drivers by identifying their significant cis-effects and distal trans-effects quantified at the RNA, protein, and phosphoprotein levels. Salient observations include the association of point mutations and copy-number alterations with the rewiring of protein interaction networks, and notably, most cancer genes converge toward similar molecular states denoted by sequence-based kinase activity profiles. A correlation between predicted neoantigen burden and measured T cell infiltration suggests potential vulnerabilities for immunotherapies. Patterns of cancer hallmarks vary by polygenic protein abundance ranging from uniform to heterogeneous. Overall, our work demonstrates the value of comprehensive proteogenomics in understanding the functional states of oncogenic drivers and their links to cancer development, surpassing the limitations of studying individual cancer types.
Topics: Humans; Proteogenomics; Neoplasms; Oncogenes; Cell Transformation, Neoplastic; DNA Copy Number Variations
PubMed: 37582357
DOI: 10.1016/j.cell.2023.07.014 -
CA: a Cancer Journal For Clinicians 2023Cancer development is driven by the accumulation of alterations affecting the structure and function of the genome. Whereas genetic changes disrupt the DNA sequence,... (Review)
Review
Cancer development is driven by the accumulation of alterations affecting the structure and function of the genome. Whereas genetic changes disrupt the DNA sequence, epigenetic alterations contribute to the acquisition of hallmark tumor capabilities by regulating gene expression programs that promote tumorigenesis. Shifts in DNA methylation and histone mark patterns, the two main epigenetic modifications, orchestrate tumor progression and metastasis. These cancer-specific events have been exploited as useful tools for diagnosis, monitoring, and treatment choice to aid clinical decision making. Moreover, the reversibility of epigenetic modifications, in contrast to the irreversibility of genetic changes, has made the epigenetic machinery an attractive target for drug development. This review summarizes the most advanced applications of epigenetic biomarkers and epigenetic drugs in the clinical setting, highlighting commercially available DNA methylation-based assays and epigenetic drugs already approved by the US Food and Drug Administration.
Topics: Humans; Epigenesis, Genetic; Neoplasms; DNA Methylation; Cell Transformation, Neoplastic
PubMed: 36512337
DOI: 10.3322/caac.21765 -
Nature Cancer Aug 2023Cell plasticity represents the ability of cells to be reprogrammed and to change their fate and identity, enabling homeostasis restoration and tissue regeneration... (Review)
Review
Cell plasticity represents the ability of cells to be reprogrammed and to change their fate and identity, enabling homeostasis restoration and tissue regeneration following damage. Cell plasticity also contributes to pathological conditions, such as cancer, enabling cells to acquire new phenotypic and functional features by transiting across distinct cell states that contribute to tumor initiation, progression, metastasis and resistance to therapy. Here, we review the intrinsic and extrinsic mechanisms driving cell plasticity that promote tumor growth and proliferation as well as metastasis and drug tolerance. Finally, we discuss how cell plasticity could be exploited for anti-cancer therapy.
Topics: Humans; Cell Plasticity; Neoplasms; Cell Transformation, Neoplastic; Homeostasis
PubMed: 37537300
DOI: 10.1038/s43018-023-00595-y -
Cell Feb 2024Streptococcus anginosus (S. anginosus) was enriched in the gastric mucosa of patients with gastric cancer (GC). Here, we show that S. anginosus colonized the mouse...
Streptococcus anginosus (S. anginosus) was enriched in the gastric mucosa of patients with gastric cancer (GC). Here, we show that S. anginosus colonized the mouse stomach and induced acute gastritis. S. anginosus infection spontaneously induced progressive chronic gastritis, parietal cell atrophy, mucinous metaplasia, and dysplasia in conventional mice, and the findings were confirmed in germ-free mice. In addition, S. anginosus accelerated GC progression in carcinogen-induced gastric tumorigenesis and YTN16 GC cell allografts. Consistently, S. anginosus disrupted gastric barrier function, promoted cell proliferation, and inhibited apoptosis. Mechanistically, we identified an S. anginosus surface protein, TMPC, that interacts with Annexin A2 (ANXA2) receptor on gastric epithelial cells. Interaction of TMPC with ANXA2 mediated attachment and colonization of S. anginosus and induced mitogen-activated protein kinase (MAPK) activation. ANXA2 knockout abrogated the induction of MAPK by S. anginosus. Thus, this study reveals S. anginosus as a pathogen that promotes gastric tumorigenesis via direct interactions with gastric epithelial cells in the TMPC-ANXA2-MAPK axis.
Topics: Animals; Humans; Mice; Atrophy; Carcinogenesis; Cell Transformation, Neoplastic; Gastric Mucosa; Gastritis; Inflammation; Mitogen-Activated Protein Kinases; Stomach Neoplasms; Streptococcus anginosus; Streptococcal Infections
PubMed: 38295787
DOI: 10.1016/j.cell.2024.01.004 -
Cancer Discovery Jul 2023Inflammation is strongly associated with pancreatic ductal adenocarcinoma (PDAC), a highly lethal malignancy. Dysregulated RNA splicing factors have been widely reported...
UNLABELLED
Inflammation is strongly associated with pancreatic ductal adenocarcinoma (PDAC), a highly lethal malignancy. Dysregulated RNA splicing factors have been widely reported in tumorigenesis, but their involvement in pancreatitis and PDAC is not well understood. Here, we report that the splicing factor SRSF1 is highly expressed in pancreatitis, PDAC precursor lesions, and tumors. Increased SRSF1 is sufficient to induce pancreatitis and accelerate KRASG12D-mediated PDAC. Mechanistically, SRSF1 activates MAPK signaling-partly by upregulating interleukin 1 receptor type 1 (IL1R1) through alternative-splicing-regulated mRNA stability. Additionally, SRSF1 protein is destabilized through a negative feedback mechanism in phenotypically normal epithelial cells expressing KRASG12D in mouse pancreas and in pancreas organoids acutely expressing KRASG12D, buffering MAPK signaling and maintaining pancreas cell homeostasis. This negative feedback regulation of SRSF1 is overcome by hyperactive MYC, facilitating PDAC tumorigenesis. Our findings implicate SRSF1 in the etiology of pancreatitis and PDAC, and point to SRSF1-misregulated alternative splicing as a potential therapeutic target.
SIGNIFICANCE
We describe the regulation of splicing factor SRSF1 expression in the context of pancreas cell identity, plasticity, and inflammation. SRSF1 protein downregulation is involved in a negative feedback cellular response to KRASG12D expression, contributing to pancreas cell homeostasis. Conversely, upregulated SRSF1 promotes pancreatitis and accelerates KRASG12D-mediated tumorigenesis through enhanced IL1 and MAPK signaling. This article is highlighted in the In This Issue feature, p. 1501.
Topics: Animals; Mice; Alternative Splicing; Carcinogenesis; Carcinoma, Pancreatic Ductal; Cell Transformation, Neoplastic; Inflammation; Pancreatic Neoplasms; Pancreatitis; RNA Splicing Factors; Serine-Arginine Splicing Factors; Humans
PubMed: 37098965
DOI: 10.1158/2159-8290.CD-22-1013 -
Cell Proliferation Oct 2023Lactate is not only an endpoint of glycolysis but is gradually being discovered to play the role of a universal metabolic fuel for energy via the 'lactate shuttle'... (Review)
Review
Lactate is not only an endpoint of glycolysis but is gradually being discovered to play the role of a universal metabolic fuel for energy via the 'lactate shuttle' moving between cells and transmitting signals. The glycolytic-dependent metabolism found in tumours and fast-growing cells has made lactate a pivotal player in energy metabolism reprogramming, which enables cells to obtain abundant energy in a short time. Moreover, lactate can provide favourable conditions for tumorigenesis by shaping the acidic tumour microenvironment, recruiting immune cells, etc. and the recently discovered lactate-induced lactylation moves even further on pro-tumorigenesis mechanisms of lactate production, circulation and utilization. As with other epigenetic modifications, lactylation can modify histone proteins to alter the spatial configuration of chromatin, affect DNA accessibility and regulate the expression of corresponding genes. What's more, the degree of lactylation is inseparable from the spatialized lactate concentration, which builds a bridge between epigenetics and metabolic reprogramming. Here, we review the important role of lactate in energy reprogramming, summarize the latest finding of lactylation in tumorigenesis and try to explore therapeutic strategies in oncotherapy that can kill two birds with one stone.
Topics: Humans; Lactic Acid; Neoplasms; Carcinogenesis; Histones; Cell Transformation, Neoplastic; Epigenesis, Genetic; Tumor Microenvironment
PubMed: 37060186
DOI: 10.1111/cpr.13478 -
Gut Jul 2023Biological insights into the stepwise development and progression of colorectal cancer (CRC) are imperative to develop tailored approaches for early detection and...
OBJECTIVE
Biological insights into the stepwise development and progression of colorectal cancer (CRC) are imperative to develop tailored approaches for early detection and optimal clinical management of this disease. Here, we aimed to dissect the transcriptional and immunologic alterations that accompany malignant transformation in CRC and to identify clinically relevant biomarkers through spatial profiling of pT1 CRC samples.
DESIGN
We employed digital spatial profiling (GeoMx) on eight pT1 CRCs to study gene expression in the epithelial and stromal segments across regions of distinct histology, including normal mucosa, low-grade and high-grade dysplasia and cancer. Consecutive histology sections were profiled by imaging mass cytometry to reveal immune contextures. Finally, publicly available single-cell RNA-sequencing data was analysed to determine the cellular origin of relevant transcripts.
RESULTS
Comparison of gene expression between regions within pT1 CRC samples identified differentially expressed genes in the epithelium (n=1394 genes) and the stromal segments (n=1145 genes) across distinct histologies. Pathway analysis identified an early onset of inflammatory responses during malignant transformation, typified by upregulation of gene signatures such as innate immune sensing. We detected increased infiltration of myeloid cells and a shift in macrophage populations from pro-inflammatory HLA-DRCD204 macrophages to HLA-DRCD204 immune-suppressive subsets from normal tissue through dysplasia to cancer, accompanied by the upregulation of the CD47/SIRPα 'don't eat me signal'.
CONCLUSION
Spatial profiling revealed the molecular and immunological landscape of CRC tumourigenesis at early disease stage. We identified biomarkers with strong association with disease progression as well as targetable immune processes that are exploitable in a clinical setting.
Topics: Humans; Transcriptome; Colorectal Neoplasms; Gene Expression Profiling; Cell Transformation, Neoplastic; Biomarkers
PubMed: 36442992
DOI: 10.1136/gutjnl-2022-327608 -
Nature Jan 2024Oncogene-induced replication stress generates endogenous DNA damage that activates cGAS-STING-mediated signalling and tumour suppression. However, the precise mechanism...
Oncogene-induced replication stress generates endogenous DNA damage that activates cGAS-STING-mediated signalling and tumour suppression. However, the precise mechanism of cGAS activation by endogenous DNA damage remains enigmatic, particularly given that high-affinity histone acidic patch (AP) binding constitutively inhibits cGAS by sterically hindering its activation by double-stranded DNA (dsDNA). Here we report that the DNA double-strand break sensor MRE11 suppresses mammary tumorigenesis through a pivotal role in regulating cGAS activation. We demonstrate that binding of the MRE11-RAD50-NBN complex to nucleosome fragments is necessary to displace cGAS from acidic-patch-mediated sequestration, which enables its mobilization and activation by dsDNA. MRE11 is therefore essential for cGAS activation in response to oncogenic stress, cytosolic dsDNA and ionizing radiation. Furthermore, MRE11-dependent cGAS activation promotes ZBP1-RIPK3-MLKL-mediated necroptosis, which is essential to suppress oncogenic proliferation and breast tumorigenesis. Notably, downregulation of ZBP1 in human triple-negative breast cancer is associated with increased genome instability, immune suppression and poor patient prognosis. These findings establish MRE11 as a crucial mediator that links DNA damage and cGAS activation, resulting in tumour suppression through ZBP1-dependent necroptosis.
Topics: Humans; Cell Proliferation; Cell Transformation, Neoplastic; DNA Damage; MRE11 Homologue Protein; Necroptosis; Nucleosomes; Nucleotidyltransferases; Radiation, Ionizing; Triple Negative Breast Neoplasms; Genomic Instability
PubMed: 38200309
DOI: 10.1038/s41586-023-06889-6